Ca2+-activated potassium (K) channels consist of at least three subtypes: Big- (BK), Intermediate- (IK) and Small-conductance K channel. These channels are activated by increase in intracellular Ca2+ level. Although BK and IK channels are sensitive to changes in membrane voltage and increase in intracellular Ca2+ level, SK channels are not significantly sensitive to the change in membrane voltage. Besides, SK channels are characterized in that the channels have a low conductance of 6 to 20 pS to single channel and a higher sensitivity to apamin. SK channels are present not only in excitable cells such as nerve cells and muscle cells but also in other kinds of cells such as liver cells or blood cells, and may be responsible for various cell functions including chemokine release, muscle contraction and secretion.
Apamin is a well-known selective SK channel blocker, and it has been reported that this agent activates gastrointestinal peristaltic function (S. A. Waterman and M. Costa, J. Physiology 477, 459-468, 1994; N. Spencer et al., J. Physiology 517, 889-898, 1999), improves cognitive/acquisition deficits (S. Ikonen et al., Eur. J. Pharmacol. 347, 13-21, 1998; C. Ghelardini et al., Br. J. Pharmacol. 123, 1079-1084, 1998) and decreases immobility time in mouse forced swimming test (N. Galeotti et al., Br. J. Pharmacol. 126, 1653-1659, 1999). Moreover, it is reported that a specific receptor for apamin exists in skeletal muscle cells and administration of this agent alleviates the symptoms in patients with myotonic muscle dystrophy (J. F. Renaud et al., Nature 319, 678-680, 1986; M. I Behrens et al., Muscle & Nerve 17, 1264-1270, 1994). Furthermore, it was reported that mice showed abnormal respiratory responses to hypoxia under conditional overexpression of SK subtype (SK3) (C. T. Bond et al., Science 289, 1942-1946, 2000).
As compounds having a SK channel-blocking activity, bis(benzimidazol) compounds such as 1,1′-(α,α′-p-xylene)-3,3′-(α,α′-m-xylene)-bis(benzimidazolium), cyclophan compounds such as 7,18-diaza-3,4(1,4)-dibenzena-1,6(1,4)-diquinolin-acyclooctadecaphan 3 trifluoroacetate hydrate, cross-linked bisquinoline compounds such as 1,4-bis-(2-methyl-quinolin-4-yl)-[1,4]-diazepane and compounds having a cyclohexane-1,1′(2′H)-spiroisoquinoline moiety are disclosed in International Patent Publication WO00/01676, WO97/48705, the U.S. Pat. No. 5,866,562 and WO02/79189, respectively.